Synthesis of 2-acyl substituted chromanes and intermediates thereof

ABSTRACT

Novel processes for producing enantiomerically enriched and enantiomerically pure compositions of 2-acyl substituted chromane compounds, and 2-acylchromane compounds that are intermediates for producing platelet aggregation inhibitors and/or are themselves potent platelet aggregation inhibitors are disclosed. Further disclosed are processes for producing salts such as acid addition salts for such enantiomerically enriched compositions.

This is the U.S. national phase under 35 U.S.C. §371 of Internationalapplication PCT/US01/17667, published in English, filed Jun. 1, 2001,which claims priority to U.S. Provisional Application Nos. 60/208,588,filed Jun. 2, 2000; and 60/208,764, filed Jun. 2, 2000.

FIELD OF THE INVENTION

This invention relates to novel processes for producing enantiomericallyenriched and substantially enantiomerically pure compositions of 2-acylsubstituted chromane compounds, and 2-acylchromane compounds that areintermediates for producing platelet aggregation inhibitors and/or arethemselves potent platelet aggregation inhibitors. Further, theinvention relates to processes for producing salts such as acid additionsalts for such enantiomerically enriched compositions.

BACKGROUND OF THE INVENTION

The production of 2-acyl-4-oxo-chromenes (2-acylchromones) by ringclosure or substituted benzene ring structures are well known in theart. One known initial process step for the production of4-oxochromene-2-carboxylic acid, or derivatives of such acids includingacid halides or esters, uses 2-hydroxy-acetophenone compounds asstarting materials. (See e.g., J. Med. Chem., Vol. 15, No. 8, 1972.) Thereaction scheme to produce the 2-carboxylic acid and esters is asfollows:

where X is ethyl, for example. The acid can be converted to an acylhalide, such as acyl chloride, instead of the ethyl ester by reacting itwith SOCl₂, for example. A further reaction of the acyl chloride withNH₃ can be used to produce the carboxamide.

The above chromene-derivative compounds have been reported as usefulintermediates for the production of compounds wherein the phenyl ring ofthe chromene ring structure is further substituted by a benzoylaminoderivative to produce antidepressants. See, for example, U.S. Pat. No.5,659,051.

One synthesis of racemic 2-(chroman4-one-2-yl)acetic acid derivativesbegins with treating a coumarin derivative with a reducing agent such asdiisoamylborane, lithium tri-butoxyaluminohydride, lithiumtriethylborohydride, lithium trimethoxyaluminium hydride, sodiumborohydride, H₂/Pd/C, or the like. The reagent and reaction conditionsmay be selected to reduce either the α,β-double bond to the alkane, orthe lactone to a lactol, or both. In a preferred aspect of theinvention, lithium tri-butoxyaluminohydride, LiAlH₄ is used to reducethe lactone at the 2-position to a lactol.

The lactol hydroxyl group may be converted into a carboxymethyl group bystandard chain extension/replacement reactions. For example, treatingthe lactol with chloroacetate under basic conditions, for example in thepresence of pyridine, results in a carboxymethyl group at the2-position.

SUMMARY OF THE INVENTION

The present invention relates to novel processes for producingenantiomerically enriched or substantially enantiomerically purecompositions of 2-chromanylcarboxylic acid compounds and2-chromanylacetic acid esters, which are intermediates for producingtherapeutic agents, or are themselves therapeutic agents for diseasestates in mammals that have disorders caused by or impacted by plateletdependent narrowing of the blood supply.

In accordance with a preferred embodiment, there is provided a processfor making a compound according to the formula

wherein R is H or an alkyl group. The process comprises (a) through (f):

(a) hydrogenating a compound of the formula:

to produce a compound of the formula:

(b) reducing the carboxylic acid of compound of (a) to afford a compoundas follows:

(c) transforming the hydroxyl group of compound of (b) into a leavinggroup to afford a compound as follows:

wherein OLG is a leaving group attached to oxygen;

(d) reacting the compound of (c) with cyanide ion to afford a compoundas follows:

(e) hydrolyzing the compound of (d) to afford a compound as follows:

(f) optionally adding an alkyl group to form an ester.

In preferred embodiments, the hydrogenation of (a) is performed withH₂/Pd/C, and/or the reduction of (b) is performed with a chemicalreducing agent, preferably lithium aluminum hydride, borane, or aluminumhydride.

In preferred embodiments the OLG of (c) is tosylate, mesylate, orhalogen, and/or the hydrolysis (e) is performed with heating thecompound made in (d) in aqueous mineral acid, preferably hydrochloricacid.

In one preferred embodiment, (e) and (f) are performed in one reactionmixture containing reagents comprising a mineral acid and an alcohol.Preferably the mineral acid is hydrochloric acid and the alcohol isethanol.

In accordance with another preferred embodiment, there is provided aprocess for making a compound according to the formula

wherein R is H or an alkyl group. The process comprises (a) through (e):

(a) halogenating a compound of the formula:

to produce a 2-hydroxy chromane compound of the formula:

wherein X is a halogen;

(b) reacting the compound of (a) with cyanide ion to afford a compoundas follows:

(c) hydrolyzing the compound of (b) to afford a compound as follows:

(d) reducing the keto group and nitro groups of compound of (c) byhydrogenation to afford a compound as follows:

(e) optionally adding an alkyl group to form an ester.

In a preferred embodiment, the halogenation (a) is performed withthionyl chloride, thereby producing a compound of the formula:

In preferred embodiments, the hydrolysis (c) is performed with heatingthe compound formed in (h) in aqueous mineral acid, preferablyhydrochloric acid, the hydrogenation of step (d) is performed withH₂/Pd/C, and/or the esterification step (e) is performed with a mineralacid and an alcohol, preferably hydrochloric acid and ethanol.

In accordance with another preferred embodiment, there is provided aprocess for making a compound according to the formula

wherein R is H or an alkyl group. The process comprises (a) through (f):

(a) hydrogenating a compound of the formula and adding a protectinggroup to a subsequently formed amine:

to produce a compound of the formula:

(b) reducing the ketone of the lactone of compound of (a) to afford acompound as follows:

(c) transforming the hydroxyl group of compound of (b) into a carbonchain with a carbon nucleophile to afford a compound as follows:

wherein R is an alkyl group;

(d) hydrolyzing the compound of (c) to remove the alkyl group from theester to afford a compound as follows:

(e) removing the protecting group from the amine, thereby obtaining thecompound of the formula:

(f) optionally adding an alkyl group to form an ester.

In a preferred embodiment, the hydrogenation (a) is performed withH₂/Pd/C, the reduction (b) is performed with chemical reducing agentspreferably DIBAL-H, the carbon nucleophile of (c) is a phosphorus ylidepreferably (carbethoxymethylene) triphenyl-phosphine, and/or PG is t-BOCor acetyl.

In preferred embodiments, the foregoing processes make a compoundaccording to the formula:

in greater than 95% enantiomeric purity with respect to thecorresponding (2R) enantiomer, by one of the foregoing processes furthercomprising:

(i) resolving the racemate; and

(ii) forming the hydrochloride salt of the resolved amine compound.

In accordance with another preferred embodiment, there is provided aprocess for making a compound according to the formula

wherein R is an alkyl group and Z is a counterion to the amine salt. Theprocess comprises:

(a) hydrogenating the compound of the formula:

wherein Y is a nitro, amino or protected amino group, with a chiralcatalyst to afford a compound as follows:

(b) optionally reducing the nitro group of compound of (a) byhydrogenation to afford a compound as follows or removing the aminoprotecting group to produce a compound of the formula:

(c) forming the amine salt by reaction of compound of (b) with a mineralacid.

In preferred embodiments, the chiral catalyst comprises ruthenium,rhodium, palladium or platinum.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

There is a need for improved processes for producing enantiomericallyenriched or substantially enantiomerically pure compounds andintermediates for the synthesis of platelet aggregation inhibitors inwhich the benzene ring of the benzopyran is substituted differently thanfor the antidepressants reported in U.S. Pat. No. 5,659,051; andfurther, in which the 4-keto group is reduced to a methylene group, andthe 2,3-double bond of the pyran is saturated. The procedures outlinedabove provide routes to these reduced species as chromane carboxylicacids. Thus, there is a need for an inexpensive, large-scale process forresolving these chiral benzopyran or chromane compounds intoenantiomerically enriched or substantially enantiomerically purecompositions. Inherent losses of at least 50% of the starting materialin any enantiomeric resolution require that the process be sufficientlyefficient and inexpensive to be run on the industrial scale necessary toproduce the large quantities of intermediate or final 2-chromanylaceticacid compounds needed for anticoagulant applications. A procedure thatregenerates the racemate from the undesired enantiomer would improve theoverall efficiency of the resolution process by allowing improvedrecoveries of the desired enantiomer.

One or more of the foregoing needs may be met using the processesdescribed herein and the compounds and intermediates made thereby.

In particular, the present invention provides a process comprising aracemate resolution step as follows:

R is a substituent on the benzene ring such as amino, a protected aminogroup such as benzamido or acetamido, or a group that can be convertedto an amino group (e.g., hydrogen or halogen). R¹ is hydrogen or alkylgroup. Preferably, the 2-carboxylic acid group is esterified with amethyl or ethyl group and the R group on the benzene portion is nitro,amino, or protected amino. More preferably, R is an acyl protected aminogroup, e.g., acetamido or benzamido.

In a preferred aspect of this invention, the amino group is at the6-position of the benzene ring and is protected, for example asacetamido. We have discovered that alaninol and racemic chromanecarboxylic acids form diastereomeric salts that are unexpectedly easy toseparate. When D-alaninol is used, S-chromane salts are recovered ascrystals from methanol; when L-alaninol is used, R-chromane salts arerecovered as crystals from methanol. Alternatively, when D-alaninol isused, R-chromanes are recovered from the supernatant. Likewise, whenL-alaninol is used, S-chromanes are recovered from the supernatant. Theyield is about 40-50% of 95% or greater purity of the desired, crudediastereomer. Essentially diastereomerically pure material can beobtained from the crude diastereomer by refluxing in methanol. Yieldsmay be optimized by varying the amount of methanol used in this step.

Optionally, the amino group on the benzene ring of the compound can bedeprotected after removing the alaninol, and the free acid esterifiedwith an acidic alcohol solution. Also, a mineral acid salt such as thehydrochloride salt of the amino group may be formed by exposing thecompound to the mineral acid such as hydrochloric acid, preferably in aone pot process at the end of the ester formation by increasing themineral acid content.

Where the 2-hydroxyacetophenone starting material of the Allan-Robinsonreaction does not contain a nitro or amino group, neither will chromoneproduct of that reaction. This chromone (3) may be nitrated at the6-position as shown:

The major product is nitration at the 6-position as shown in product 3a.The nitro group may also be introduced by other means, such asbrominating the chromone followed by substituting the bromine withnitro, for example. The direct nitration is preferred, however, as morestraightforward.

Reducing the chromone (3 or 3a) 4-keto group and 2,3-double bondproduces a chromane ring system, conditions under which the nitro groupon the benzene ring may also be reduced to an amine. Standard reductionconditions, including catalytic hydrogenation and use of chemicalreducing agents—for example, diisoamylborane, lithiumtri-butoxyaluminohydride, H₂/Pd/C, and the like—may be used. In apreferred aspect, lithium tri-butoxyaluminohydride or LiAlH₄ alsoreduces the carboxylate ester at the 2-position to a hydroxymethyl group(compound 4).

An example of the conversion of the keto compound to the chromane coreis as follows:

In this example, a nitro group in the starting material is reduced to anamino group, which is preferably in the 6-position on the chromane ringas shown:

This compound may be further modified by converting the 2-hydroxymethylinto a chromanyl-substituted acetic acid or acetic acid ester, asfollows:

Here, R¹ is preferably an ethyl group. As shown above, the free aminemay be tosylated in the step in which cyanide replaces hydroxyl. Thetosyl group may be removed concomitant with the hydrolysis of thenitrile to the carboxylate with excess concentrated HCl. Alternatively,after nitrile hydrolysis, the hydrochloric acid may be removed from thereaction mixture—by neutralization of the solution and recrystallizationof the product from isopropyl alcohol, for example—and a morenucleophilic acid such as hydrobromic acid may be used to hydrolyze thetoluenesulfonamide. In such circumstances, care should be taken to avoidconverting the carboxylic acid into an acyl bromide.

In an alternative embodiment of the present invention, compound 3(above, acid or ester) may be converted first into an acyl halide, thenthe halide replaced with a cyano group to produce an α-ketonitrile, Theα-ketonitrile may be hydrolyzed with a strong acid to form anα-ketocarboxylic acid, which may be catalytically hydrogenated inglacial acetic acid to produce chroman-2-ylacetate esters. Thisprocedure avoids multiple hydrogenation steps or reducing the carboxylgroup to hydroxymethyl before adding the nitrile. In a preferred aspect,the nitro group at the 6-position is retained until it is converted toan amino group during the hydrogenation step. In a further preferredaspect, compound 1 is 2-hydroxyacetophenone and the ester form ofcompound 3 is nitrated prior to conversion into the acyl halide. Thisprocedure obviates the amine sulfonylation-desulfonylation reactionsneeded in the hydride reduction process.

In the following illustration, steps 1a and 2a show the conversion ofcompound 3 into an acyl halide (here, chloride) and the substitution ofthe halide by CN:

Preferably, the R group is nitro, which can later be reduced to amino.More preferably, the nitro is at the 6-position of the chromone. Theα-ketonitrile at the 2-position is converted into an α-ketocarboxylicacid with a strong mineral acid, such as hydrochloric acid, as follows:

Preferably, the chromone keto group, the 2-keto substituent, the nitrogroup, and the 2,3-double bond are hydrogenated in a single step.However, in one embodiment, the hydrogenation is conducted in two steps.The first step is hydrogenation under mild conditions in the presence ofan alcohol, such as methanol, ethanol, or the like; or in ethyl acetateor the like, at about 30 psi of hydrogen for about 1-2 h, followed bypurging the apparatus with nitrogen, then hydrogen. In the second step,glacial acetic acid is added to the reaction mixture, the hydrogenpressure is increased to 45-65 psi, and the temperature raised tobetween 50-95° C. until the hydrogenation is complete. The progress ofeach of these reactions may be monitored by HPLC. While thehydrogenation may be viewed as either a one-step or two-step process, itis a one-pot procedure preferably requiring no separation step.

The procedure performed in a single hydrogenation step may beexemplified as follows:

This procedure provides the racemic ethyl chroman-2-ylacetate compoundsin good yield. These compounds may optionally be resolved as set forthbelow.

If desired, the chroman-2-ylacetate esters may be resolved throughmethods well known in the art. For example, the ester group may bemodified with conventional resolving agents such as camphorsulfonic acidderivatives, dibenzoyltartaric acid derivatives, and the like.Alternatively, one enantiomer of the ester may selectively hydrolyzedenzymatically. The amino group may be oxidized to a nitro group whoseelectron-withdrawing character aids the hydrolysis reaction, or theresolution step may be done prior to reducing the nitro group to anamine as shown above.

In this example, the ethyl ester of the S-enantiomer is the product ofthe reesterification of the resolved carboxylic acid; however, otheresters, such as the methyl or propyl, may likewise be envisioned.Hydrochloric acid in the reesterification step also converts the amineto its hydrochloride salt. In general, where the desired enantiomer isobtained as the carboxylic acid, treatment with ethanol and an excess ofhydrochloric acid produces the ethyl ester of the carboxylic acid andthe hydrochloride salt of the amine. The preferred recrystallizationsolvent for the resolved compounds is methanol or isopropanol. In apreferred aspect, the efficiency of the enzymatic resolution isincreased by converting the 6-amino group into a 6-nitro group prior tothe resolution and reconverting it into an amino group afterwards.

In a preferred aspect of the invention, the undesired enantiomer isconverted into the racemate through a process comprising at least onering-opening and one ring-closing step. This regenerated racemate isresubjected to the resolution procedure, thereby increasing the overallyield of the desired enantiomer, and consequently, the overallefficiency of the resolution.

In the syntheses of these compounds, amine or carboxylic acid groups maybe protected to prevent undesired reactions of that functional group.Examples of suitable protecting groups are well known in the art.Furthermore, methods for removing these protecting groups, for exampleby hydrolysis or hydrogenolysis, are well known in the art.

Some non-limiting, exemplary synthetic schemes, each of which is apreferred embodiment of the invention, comprise the process stepsoutlined below. These synthetic schemes may include additional stepsprecedent, such as those set forth in J. Med. Chem., Vol. 15, No. 8(1972), or steps subsequent, for example converting the amine group intoa different group, such as one affecting anticoagulant activity. Suchmodifications are advantageously effected through amine couplingreactions, which are well known in the art. The specific steps set forthin the schemes below are described in the Examples. In general, thereaction products are isolated and purified by conventional methods,typically by solvent extraction into a compatible solvent. Preferredsolvents are lower alkane ethers and alcohols; ethyl ether and isopropylalcohol are preferred for solvent extraction and recrystallization.L-alaninol is the preferred resolving agent since it is typically lessexpensive than D-alaninol, but other resolving agents or analogousprocedures may be used. The products may be further purified by columnchromatography or by other appropriate methods.

In the schemes shown above, the order of some of the reactions may bereversed, some (e.g. chain extension and nitration) some reactions maybe omitted (e.g. a final esterification or salt formation step), andreactions from other schemes may be substituted in for other reactionshaving similar results. Additionally, other reagents and conditionshaving similar results may be substituted for those disclosed. Forreactions producing racemates, resolution of a racemate may occur at anysuitable place in the scheme and may proceed with reagents other thanlipase, a preferred reagent and process disclosed herein. Furthermore,salts and esters may be formed and/or interconverted with thecorresponding free acid or base as desired at any place in the scheme ifdesired, such as to aid in isolation or purification of a compound orintermediate.

In other embodiments, the order of some of the reactions in the schemesmay be changed, and additional steps of protecting, deprotecting,nitrating, hydrolyzing, esterifying, and the like may be added to theschemes at various points. Such minor alterations are within the scopeof the disclosure herein. Although the esters shown are primarily ethylesters, other esters may be made, either by use of different solventsand/or reagents in the initial formation reactions or bytransesterification.

The starting materials used in the disclosed processes are commerciallyavailable from chemical vendors such as Aldrich, Lancaster, TCl, BachemBiosciences, and the like, or may be readily synthesized by knownprocedures including those present in the chemical literature, or may bemade by using procedures such as indicated above.

Reactions are carried out in standard laboratory glassware and reactionvessels under reaction conditions of standard temperature and pressure,except where it is otherwise indicated, or where use of non-STPconditions for a procedure is known in the art. Some procedures,reactions, and/or workups which are well known in the art or which arereadily available in standard reference texts in the art, includingBeilstein and Fieser and Fieser, may not be presented herein owing totheir stature of being within the knowledge of one of ordinary skill.Further, the above procedures of the processes may be carried out on acommercial scale by utilizing reactors and standard scale-up equipmentavailable in the art for producing large amounts of compounds in thecommercial environment. Such equipment and scale-up procedures are knownto the ordinary practitioner in the field of commercial chemicalproduction.

During the synthesis of these compounds, amino or acid functional groupsmay be protected by blocking groups to prevent undesired reactions withthe amino group during certain procedures. Procedures for suchprotection and removal of protecting groups are routine and well knownto the ordinary practitioner in this field.

Enantiomeric Resolution and Acid Salt Formation

When a reaction results in the production of racemic chroman-2-ylcarboxylic acids and esters, these racemates are preferably resolved toproduce a mixture enriched in one of the R or S enantiomers orcompletely resolved into a substantially pure composition of one of theenantiomers. Examples of processes for resolving the racemic mixturesare provided herein and/or are known to those skilled in the art.Additionally, processes for the formation of acid addition salts such asthe hydrochloride salt of the 6-position amino acid group on thechromane nucleus are known in the art. Other such salts are alsoenvisioned.

Uses of Compounds

As mentioned above, the compounds produced according to preferredembodiments find utility as intermediates for producing therapeuticagents or as therapeutic agents for disease states in mammals, includingthose which have disorders that are due to platelet dependent narrowingof the blood vessels, such as atherosclerosis and arteriosclerosis,acute myocardial infarction, chronic stable angina, unstable angina,transient ischemic attacks and strokes, peripheral vascular disease,arterial thrombosis, preeclampsia, embolism, restenosis followingangioplasty, carotid endarterectomy, anastomosis of vascular grafts, andetc. These conditions represent a variety of disorders thought to beinitiated by platelet activation on vessel walls.

Platelet adhesion and aggregation is believed to be an important part ofthrombus formation. This activity is mediated by a number of plateletadhesive glycoproteins. The binding sites for fibrinogen, fibronectinand other clotting factors have been located on the platelet membraneglycoprotein complex IIb/IIIa. When a platelet is activated by anagonist such as thrombin, the GP IIb/IIIa binding site becomes availableto fibrinogen, eventually resulting in platelet aggregation and clotformation. Thus, intermediate compounds for producing compounds thateffective in the inhibition of platelet aggregation and reduction of theincidence of clot formation are useful intermediate compounds.

The compounds produced according to preferred embodiments may also beused as intermediates to form compounds that may be administered incombination or concert with other therapeutic or diagnostic agents. Incertain preferred embodiments, the compounds produced by theintermediates according to the present invention may be co-administeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice such as anticoagulantagents, thrombolytic agents, or other antithrombotics, includingplatelet aggregation inhibitors, tissue plasminogen activators,urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.The compounds produced from the intermediates may act in a synergisticfashion to prevent reocclusion following a successful thrombolytictherapy and/or reduce the time to reperfusion. Such compounds may alsoallow for reduced doses of the thrombolytic agents to be used andtherefore minimize potential hemorrhagic side-effects. Such compoundscan be utilized in vivo, ordinarily in mammals such as primates, (e.g.humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or invitro.

Coupling Reaction of the Hydrochloride Salt Intermediate Compounds

The above compounds produced according to preferred methods may beisolated and further reacted to substitute a desired group for one ormore of the hydrogen atoms on the amino group by a coupling reaction.Particularly preferred is a coupling reaction of the amino group with anacyl halide compound. For example, compounds such as5-amidino-thiophen-2-yl carboxylic acid derivatives (or an acyl halidesuch as the acyl chloride) and 4-amidinobenzoyl chloride may be coupledto ethyl (2S)-(6-aminochroman-2-yl) acetate (or its hydrochloride salt)to form ethyl(2S)-[6-(5-amidino-2-thiophenoyl)amino-chroman-2-yl]acetate and—ethyl(2S)-{6-[(4-amidinophenyl) carbonylamino]chroman-2-yl} acetate, or othersimilar compounds or their derivatives which are known plateletaggregation inhibitors. For examples of such platelet aggregationinhibitors, see U.S. Pat. No. 5,731,324. The ring portion of the aboveamidino-aroyl or amidino-heteroaroyl derivatives may be substituted bygroups such as methyl, ethyl, fluoro, iodo, bromo, chloro, methoxy,ethoxy, and the like which results in compounds that are known plateletaggregation inhibitors. Standard coupling procedures may be utilized,but procedures utilizing reaction mixtures the compounds, in salt form,are suspended in solvents such as acetonitrile, toluene, or the like,are preferred.

The compound formed from the coupling reaction may be used as either thesalt or the free base, and may be readily interconverted between the twoforms by using procedures which include those known in the art as wellas reacting the compound with one or more molar equivalents of thedesired acid or base in a solvent or solvent mixture in which the saltis insoluble, or in a solvent after which the solvent is removed byevaporation, distillation or freeze drying. Alternatively, the free acidor base form of the product may be passed over an ion exchange resin toform the desired salt, or one salt form of the product may be convertedto another using the same general process. The free base or salts may bepurified by various techniques such as recrystallization in a loweralkanol such as methanol, ethanol, propanol, isopropanol and the like,for example, or a mixture thereof. In preferred embodiments, thecompound is recovered as the hydrochloride salt and therecrystallization solvent is a 90/10-10/90 mixture of ethanol andisopropanol. Non-toxic and physiologically compatible salts arepreferred, although other types of salts may also be used, such as inthe processes of isolation and purification.

Compositions and Formulations

Diagnostic and therapeutic applications of the compounds formed byprocedures disclosed herein, including the aforementioned couplingreactions, will typically utilize formulations wherein the compound, ora pharmaceutically acceptable salt, solvate, or prodrug, is combinedwith one or more adjuvants, excipients, solvents, or carriers. Theformulations may exist in forms including, but not limited to tablets,capsules or elixirs for oral administration; suppositories; sterilesolutions or suspensions for injectable or parenteral administration; orincorporated into shaped articles. Subjects in need of treatment(typically mammalian) using the compounds of this invention can beadministered dosages that will provide optimal efficacy. The dose andmethod of administration will vary from subject to subject and bedependent upon such factors as the type of mammal being treated, itssex, weight, diet, concurrent medication, overall clinical condition,the particular compounds employed, the specific use for which thesecompounds are employed, and other factors which those skilled in themedical arts will recognize.

Formulations are prepared for storage or administration by mixing thecompound, or a pharmaceutically acceptable salt, solvate or prodrugthereof, having a desired degree of purity with physiologicallyacceptable carriers, excipients, stabilizers etc., and may be providedin sustained release or timed release formulations. Acceptable carriersor diluents for therapeutic use are well known in the pharmaceuticalfield, and are described, for example, in Remington's PharmaceuticalSciences, Mack Publishing Co., (A. R. Gennaro edit. 1985). Suchmaterials are nontoxic to the recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrate,acetate and other organic acid salts, antioxidants such as ascorbicacid, low molecular weight (less than about ten residues) peptides suchas polyarginine, proteins, such as serum albumin, gelatin, orimmunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone,amino acids such as glycine, glutamic acid, aspartic acid, or arginine,monosaccharides, disaccharides, and other carbohydrates includingcellulose or its derivatives, glucose, mannose or dextrins, chelatingagents such as EDTA, sugar alcohols such as mannitol or sorbitol,counter ions such as sodium and/or nonionic surfactants such as Tween,Pluronics or polyethyleneglycol.

Dosage formulations to be used for parenteral administration arepreferably sterile. Sterility is readily accomplished by filtrationthrough sterile membranes such as 0.2 micron membranes, or by other:conventional methods known to those skilled in the art. Formulations arepreferably stored in lyophilized form or as an aqueous solution. The pHof such preparations are preferably between 3 and 11, more preferablyfrom 5 to 9 and most preferably from 7 to 8. It will be understood thatuse of certain of the foregoing excipients, carriers, or stabilizerswill result in the formation of cyclic polypeptide salts. While thepreferred route of administration is by injection, other methods ofadministration are also anticipated such as intravenously (bolus and/orinfusion), subcutaneously, intramuscularly, colonically, rectally,nasally or intraperitoneally, employing a variety of dosage forms suchas suppositories, implanted pellets or small cylinders, aerosols, oraldosage formulations and topical formulations such as ointments, dropsand dermal patches. The compounds are desirably incorporated into shapedarticles such as implants which may employ inert materials such asbiodegradable polymers or synthetic silicones, for example, Silastic,silicone rubber or other polymers commercially available.

The compounds may also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety oflipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds may also be delivered by the use of antibodies, antibodyfragments, growth factors, hormones, or other targeting moieties, towhich the compound molecules are coupled. The compounds may also becoupled with suitable polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the plateletaggregation inhibitors may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound and formulation,individual determinations may be made to determine the optimal dosagerequired. The range of therapeutically effective dosages will naturallybe influenced by the route of administration, the therapeuticobjectives, and the condition of the patient. For injection byhypodermic needle, it may be assumed the dosage is delivered into thebody's fluids. For other routes of administration, the absorptionefficiency must be individually determined for each inhibitor by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect. The determination ofeffective dosage levels, that is, the dosage levels necessary to achievethe desired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferablyfrom about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compoundsor formulations may be administered several times daily, in a once dailydose, or in other dosage regimens.

Typically, about 0.5 to 500 mg of a compound or mixture of compounds, asthe free acid or base form or as a pharmaceutically acceptable salt orprodrug derivative (including esters), is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, dye, flavor etc., as called for by acceptedpharmaceutical practice. The amount of active ingredient in thesecompositions is such that a suitable dosage in the range indicated isobtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are a binder such as acacia, corn starch or gelatin, andexcipient such as microcrystalline cellulose, a disintegrating agentlike corn starch or alginic acid, a lubricant such as magnesiumstearate, a sweetening agent such as sucrose or lactose, or a flavoringagent. When a dosage form is a capsule, in addition to the abovematerials it may also contain a liquid carrier such as water, saline, afatty oil. Other materials of various types may be used as coatings oras modifiers of the physical form of the dosage unit. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice. For example, dissolution or suspension of theactive compound in a vehicle such as an oil or a synthetic fatty vehiclelike ethyl oleate, or into a liposome may be desired. Buffers,preservatives, antioxidants and the like can be incorporated accordingto accepted pharmaceutical practice.

The compounds and formulations may be used alone or in combination, orin combination with other therapeutic or diagnostic agents. In certainpreferred embodiments, the compounds and/or formulations may becoadministered along with other compounds typically prescribed for theseconditions according to generally accepted medical practice, such asanticoagulant agents, thrombolytic agents, or other antithrombotics,including platelet aggregation inhibitors, tissue plasminogenactivators, urokinase, prourokinase, streptokinase, heparin, aspirin, orwarfarin. The compounds and formulations can be utilized in vivo,ordinarily in mammals such as primates, such as humans, sheep, horses,cattle, pigs, dogs, cats, rats and mice, or in vitro.

The compounds, selected and used as disclosed herein, are believed to beuseful for preventing or treating a condition characterized by undesiredthrombosis, such as (a) the treatment or prevention of anythrombotically mediated acute coronary syndrome including myocardialinfarction, unstable angina, refractory angina, occlusive coronarythrombus occurring post-thrombolytic therapy or post-coronaryangioplasty, (b) the treatment or prevention of any thromboticallymediated cerebrovascular syndrome including embolic stroke, thromboticstroke or transient ischemic attacks, (c) the treatment or prevention ofany thrombotic syndrome occurring in the venous system including deepvenous thrombosis or pulmonary embolus occurring either spontaneously orin the setting of malignancy, surgery or trauma, (d) the treatment orprevention of any coagulopathy including disseminated intravascularcoagulation (including the setting of septic shock or other infection,surgery, pregnancy, trauma or malignancy and whether associated withmulti-organ failure or not), thrombotic thrombocytopenic purpura,thromboanginitis obliterans, or thrombotic disease associated withheparin induced thrombocytopenia, (e) the treatment or prevention ofthrombotic complications associated with extracorporeal circulation(e.g. renal dialysis, cardiopulmonary bypass or other oxygenationprocedure, plasmapheresis), (f) the treatment or prevention ofthrombotic complications associated with instrumentation (e.g. cardiacor other intravascular catheterization, intra-aortic balloon pump,coronary stent or cardiac valve), and (g) those involved with thefitting of prosthetic devices.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds disclosed hereinand practice the claimed methods. The following working examplestherefore, specifically point out preferred embodiments, and are not tobe construed as limiting in any way the remainder of the disclosure.

EXAMPLES Example 1

Production of 6-(tert-butyloxycarbonylamino)chroman-2-one

An 8-L hydrogenation reactor equipped with a stirrer, temperatureprobes, and a heating and cooling system was charged under nitrogen with125 g of 10% palladium on carbon, 300 g of powdered 3 Å molecularsieves, 1050 g of 6-nitrocoumarin, 1318 g of di-tert-butyldicarbonate,and 4.0 L of anhydrous tetrahydrofuran. The reactor was purged 5 timeswith nitrogen and then 5 times with hydrogen. The pressure of hydrogenwas maintained at 30 psi until the end of the exotherm (30° C.<T<50°C.), then the reactor was heated to about 50° C., and the hydrogenpressure increased to 60 psi. The reaction was complete in about 15 h byTLC. The reaction mixture was cooled to room temperature and purged 3times with nitrogen before it was discharged from the reactor. Thecatalyst and molecular sieves were removed by filtration through Celiteand the filter cake was washed with 1.0 L of tetrahydrofuran. Thefiltrate was concentrated to dryness at 50° C. under reduced pressure togive an off-white crude product. Recrystallization from 3.6 L of tolueneafforded 1300 g of 6-(tert-butyloxycarbonylamino)chroman-2-one. Themother liquor was concentrated to afford an additional 47 g of theproduct (93.1% overall yield).

Example 2

Production of 6-(tert-butyloxycarbonylamino)chroman-2-ol

A 22-L three-neck round-bottom flask equipped with an overhead stirrerand an addition funnel was charged under nitrogen with 7 L of anhydrousmethylene chloride and 800 g of6-(tert-butyloxycarbonylamino)chroman-2-one (Example 1). The solutionwas cooled to about −55° C., and 2.66 L of diisobutylaluminum hydride(1.58 M solution in toluene, 4.2 mol) was slowly added through theaddition funnel to the well-stirred solution. The addition rate wasadjusted to keep the temperature of the reaction was between −50° C. and−65° C. requiring about 1.5 h overall. After an additional 1 h stirring,the reaction was complete by TLC. Methanol (870 mL) of was slowly added,keeping the temperature below −50° C. The reaction mixture was warmed upto about −20° C., and 790 g of Celite and 970 mL of water were added.The mixture was warmed to room temperature and stirred vigorously for 40minutes. The mixture was filtered and the filter cake washed with 10.0 Lof methylene chloride. The filtrate and the washings were combined andthe solvent removed under reduced pressure at 50° C. The residue wastransferred with 8.0 L of toluene into a 22-L three-neck round-bottomflask and dried azeotropically by distilling off 6 L of toluene underreduced pressure at 50° C. The volume of the remaining solution wasadjusted to about 8 L with anhydrous toluene to provide a toluenesolution of 6-(tert-butyloxycarbonylamino)chroman-2-ol.

Example 3

Production of Ethyl2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate

Into the 6-(tert-butyloxycarbonylamino)chroman-2-ol toluene solution ofExample 2 (8 L) was added 1225 g of(carbethoxymethylene)triphenylphosphorane (95%) and 1.1 g of sodiumethoxide. The stirred reaction was heated to 80° C. for 2 h. Anadditional 3.2 g of sodium ethoxide was added, and the mixture stirredat 80° C. for 18 h. Because the reaction was not complete by TLC, anadditional 122 g of (carbethoxymethylene)triphenylphosphorane and 1.0 gof sodium ethoxide was added. The reaction mixture was stirred at 80° C.for 3 h after the addition. The reaction was cooled to room temperature,and 3750 g of silica gel and 7 L of toluene were added. The mixture wasstirred for 2 h, filtered, and the filter cake was washed with 2×12 L oftoluene. The filtrate and washings were combined, and the volume reducedto about 7 L by distillation under reduced pressure (T≦60° C.) toprovide a toluene solution of ethyl2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate.

Example 4

Production of Ethyl 2-(6-aminochroman-2-yl)acetate

Into the ethyl 2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetatetoluene solution of Example 3 (7 L) was added 1480 g of trifluoroaceticacid. The solution was warmed to 60° C. for 2 h. After distilling-offabout 2 L of toluene under reduced pressure (T≦60° C.), the mixture wascooled to room temperature. About 10 L of 10% (w/w) of aqueous sodiumbicarbonate was added slowly to the well-stirred mixture until the pHwas above 7. The mixture was stirred for 20 min and the aqueous fractionseparated. The aqueous fraction was extracted with 3×1 L of toluene. Thecombined organic fractions were washed with 3 L of brine, dried over 200g of anhydrous sodium sulfate, and filtered. The volume of solvent wasreduced to 6 L by distillation under reduced pressure (T≦60° C.) toprovide a toluene solution of ethyl 2-(6-aminochroman-2-yl)acetate.

Example 5

Production of ethyl 2-(6-acetamidochroman-2-yl)acetate

The ethyl 2-(6-aminochroman-2-yl)acetate toluene solution of Example 4(6 L) was cooled to −5° C. in a sodium chloride-ice bath, and 293 g ofanhydrous pyridine added in a single portion. To the well-stirredmixture was added dropwise 246 g of acetyl chloride, maintaining thetemperature between −5° C. and 5° C. The reaction was not complete byTLC after 30 min, so an additional 50 g of anhydrous pyridine and 50 gof acetyl chloride were added dropwise, and the reaction stirred for 30min. The reaction was quenched with 4 L of water, stirred for 15minutes, and the organic fraction was separated. The aqueous fractionwas extracted with 2×500 mL of toluene, and the combined toluenefractions washed with 2 L of water. Complete removal of toluene affordedethyl 2-(6-acetamidochroman-2-yl)acetate as a dark brown residue, whichwas transferred into a 12-L flask.

Example 6

Production of 2-(6-acetamidochroman-2-yl)acetic acid by saponification

To the dark brown ethyl 6-acetamidochroman-2-ylacetate of Example 5 wasadded 3.5 L of methanol and 3.5 L of 1 N aqueous sodium hydroxide. Afterstirring the reaction mixture for 2 h at room temperature, the methanolwas removed from the reaction mixture providing a dark, aqueous residue.The residue was transferred into a separatory funnel and extracted with3×2 L of methylene chloride. Between each extraction step, the aqueousfraction was distilled to remove any organic solvent. The pH of theaqueous fraction was adjusted to about 2 with 2 N hydrochloric acid,affording a sticky, dark oil, which was separated. The acidic, aqueousfraction was extracted with 3×2 L of ethyl acetate. The ethyl acetateextracts and the dark oil were combined to form a homogenous solution.This solution was washed 2×2 L of brine and dried over 100 g ofanhydrous sodium sulfate. Removing the ethyl acetate afforded a thick,blackish oil, which solidified overnight under vacuum. The dark brownsolid was dissolved in saturated aqueous sodium bicarbonate to provide ablack solution. The well-stirred, black solution was titrated with 3 Nhydrochloric acid. At about pH 7.5, a black oil began to form on thewalls of the flask. At about pH 7.0, more black oil formed, and thecolor of the solution changed from black to light yellow. The mixturewas allowed to stand for about 5 min for the black oil to settle. Thesupernatant was decanted and acidified to about pH 2.0. The resultingwhite suspension was stirred for 30 min. The precipitate was filteredand dried at 50° C. under reduced pressure affording 350 g of2-(6-acetamidochroman-2-yl)acetic acid as off-white crystals. Theoverall yield from 1347 g of 6-(tert-butyloxycarbonylamino)chroman-2-onefrom example 1 was 46.2%.

Example 7

Production of (2S)-(6-acetamidochroman-2-yl)acetic acid, D-alaninol salt

A 5-L three-neck round-bottom flask equipped with a condenser andmagnetic stirrer was charged with 1.9 L of anhydrous methanol and 240 gof 2-(6-acetamidochroman-2-yl)acetic acid (Example 8). The solution washeated to reflux, 39.8 g of D-alaninol was added in a single portion,and the reaction mixture was refluxed for 15 min. The solution wascooled to 45° C. and stirred for about 30 min. The solution was seededwith about 50 mg of (2S)-(6-acetamidochroman-2-yl)acetic acid,D-alaninol salt crystals. The solution became turbid after about 5 min,then a large amount of white crystals formed. The suspension was slowlycooled and the stirring continued at room temperature for 14 h. Thecrystals were filtered, washed with 200 mL of methanol, and dried toafford 135 g of (2S)-(6-acetamidochroman-2-yl)acetic acid, D-alaninolsalt (43.2% crude yield). The crude crystals were suspended in 2.0 L ofmethanol and heated at reflux for 8 h. The suspension was slowly cooledand allowed to stand at room temperature for a few h. The crystals werefiltered, rinsed with 15 mL of methanol, and dried to give 122 g (39.1%yield) of (2S)-(6-acetamidochroman-2-yl)Acetic Acid, D-alaninol salt.

Example 8

Production of ethyl (2S)-(6-aminochroman-2-yl)acetic acid, bisulfatesalt

A 3-L three-neck round-bottom flask equipped with a condenser and anaddition funnel was charged with 900 mL of absolute ethanol and 97.3 gof (2S)-(6-acetamidochroman-2-yl)acetic acid, D-alaninol salt (example7). To this well-stirred mixture was slowly added 92 mL of concentratedsulfuric acid through the addition funnel. The solution was refluxed for18 h, then cooled to room temperature. The cooled mixture was slowlypoured into a well-stirred mixture of 150 g of sodium bicarbonate, 800 gof ice, 600 mL of water, and 1.0 L of methylene chloride. The mixturewas stirred 20 min, and the aqueous fraction separated and extractedwith 400 mL of methylene chloride. The combined organic fractions werewashed with 600 mL of brine and concentrated to a brown residue. Theresidue was dissolved in 1.0 L of toluene, and the volume reduced to 500mL by distillation to provide ethyl (2S)-(6-aminochroman-2-yl)aceticacid, bisulfate salt as a toluene solution.

Example 9

Production of ethyl (2S)-(6-aminochroman-2-yl)acetic acid, hydrochloridesalt

A 2-L three-neck round-bottom flask equipped with a condenser and astirrer was charged with ethyl (2S)-(6-aminochroman-2-yl)acetic acid,bisulfate salt in 500 mL of toluene (Example 8). The reaction was cooledto about 10° C., and 55 mL of 5.8 M hydrochloric acid in absoluteethanol was added to the well-stirred solution. The resulting suspensionwas stirred for 17 h, then the crystals were allowed to settle. Thewhite crystals were filtered, washed with 250 mL of toluene, and driedat 60° C. under reduced pressure to afford 75 g of ethyl(2S)-(6-aminochroman-2-yl)acetic acid, hydrochloride salt (92% withrespect to (2S)-(6-acetamidochroman-2-yl)acetic acid, D-alaninol saltfrom Example 7). The product was >99% pure and the enantiomeric excesswas >99.5% by chromatography and NMR.

Example 10

Production of ethyl 6-nitrochromone-2-carboxylate

Into a solution of 12.0 g of diethyl oxalate in 180 g of toluene isadded 28 g of 5-nitro-2-hydroxyacetophenone, then dropwise added 62.0 gof 20% sodium ethoxide in ethanol. After the reaction is complete, 12.6g of 98% sulfuric acid is added, and the mixture stirred at 60° C. forabout 30 min. After adding 140 g of water, the organic fraction isseparated. The organic fraction is concentrated and 54.0 g of hexane isadded. Filtering below 10° C. affords about 33.0 g of ethyl6-nitrochromone-2-carboxylate (about 95% yield).

Example 11

Production of ethyl 6benzamidochromone-2-carboxylate

Into a solution of 12.0 g of diethyl oxalate in 180 g of toluene isadded 30 g of 5-benzamido-2-hydroxyacetophenone, then dropwise added65.0 g of 20% sodium ethoxide in ethanol. After the reaction iscomplete, 12.6 g of 98% sulfuric acid is added, and the mixture stirredat 60° C. for about 30 min. After adding 140 g of water, the organicfraction is separated. The organic fraction is concentrated and 54.0 gof hexane is added. Filtering below 10° C. affords about 36.5 g of ethyl6-benzamidochromone-2-carboxylate (about 96% yield).

Example 12

Production of ethyl 6-acetamidochromane-2-carboxylate

A hydrogenation apparatus is charged with 6 g of ethyl6-nitrochromone-2-carboxylate (Example 10), 3.5 mL of acetic anhydride,1 g of 10% palladium on carbon, 4.0 g of dry, powdered 3A molecularsieves, and 30 mL of glacial acetic acid. After purging several timeswith nitrogen, the apparatus is purged several times with hydrogen.Under continuous stirring, the apparatus is maintained at about 70 psiwith hydrogen and about 80° C. for about 10-12 h. The apparatus is thencooled to about 50° C., evacuated of hydrogen, and purged several timeswith nitrogen. Trifluororoacetic acid (3.5 mL) is added to the mixture,then the apparatus is resealed, purged several times with hydrogen, andpressurized to 70 psi with hydrogen. The stirred reaction mixture isheated to 80° C. until the reaction is complete by HPLC(intermediate:product≦3%), then cooled to room temperature. Afterfiltering the mixture through Celite, the catalyst and molecular sievesare washed with 10 mL aliquots of glacial acetic acid, and the washescombined with the filtrate. These combined filtrates are concentrated bymild distillation to an oil, which is dissolved in ethyl acetate andwashed with saturated NaHCO₃. The aqueous fraction is extracted withethyl acetate, then made strongly acidic with concentrated HCl andextracted several times with ethyl acetate. The combined ethyl acetatefractions are combined and concentrated to a solid. The solid is washedwith acetonitrile, filtered, and dried to afford about 3.5-4.0 g ofethyl 6-acetamidochromane-2-carboxylate as a white solid.

Example 13

Production of 6-acetamido-2-hydroxymethylchromane

To a solution of 3.0 grams of ethyl 6-acetamidochromane-2-carboxylate(Example 12) dissolved in 20 mL of dry ether is added dropwise asolution of 1 mL of lithium aluminum hydride (70% in benzene) dissolvedin about 2 mL of dry ether, and the solution is refluxed for about 1 h.An additional 1 mL of lithium aluminum hydride is added to the mixture,and the mixture refluxed for an additional 1-2 h. The reaction mixtureis cooled to 0° C. and the excess hydride quenched by adding 10-12 mL of1 N H₂SO₄, followed by 100 mL of water. The precipitate is filtered andwashed well with ether. The aqueous phase is separated, extractedseveral times with 60-mL aliquots of ether. The combined extracts arewashed with water and dried over anhydrous MgSO₄. Evaporation to drynessunder vacuum affords about 2.4 g of 6-acetamido-2-hydroxymethylchromane(about 90% yield).

Example 14

Production of 6-acetamido-2-cyanomethylchromane

To a solution of 2.0 g of 6-acetamido-2-hydroxymethylchromane (Example13) in 35 mL of CH₂Cl₂ and 1.5 mL of pyridine is added 2 gp-toluenesulfonyl chloride. The mixture is stirred at 25° C. for 36 h,then diluted with 20 mL ether, and washed with 10 mL. The organic layeris dried over MgSO₄ and concentrated to give 3.4 grams of the tosylate.To a stirred solution of the tosylate in 20 mL of DMSO is added 80 mg ofpowdered sodium cyanide. The mixture refluxed for 1.5 h under an inertatmosphere, then cooled, diluted with 50 mL of water, and extracted6×100 mL portions of ether. The combined ether extracts are dried overanhydrous MgSO₄ and filtered. The filtrate is concentrated and theresidue is recrystallized from ether/isopropanol to afford 1.7 grams of6-acetamido-2-cyanomethylchromane (about 85% yield).

Example 15

Production of ethyl 2-(6-aminochroman-2-yl)acetate hydrochloride

A mixture of 1.5 g of 6-acetamido-2-cyanomethylchromane (Example 14) in25 mL of concentrated hydrochloric acid is stirred vigorously at roomtemperature for about 6 h. Ethanol (50 mL) is added and the mixtureallowed to stand overnight. The precipitate is filtered, rinsed with50-mL aliquots of ether, and dried. Absolute ethanol (25 mL) and HCl (10mL) are stirred with the precipitate for 2 h, followed by addition of 10mL of concentrated HCl. The precipitate is recovered and recrystallizedtwice from ether/isopropanol affording about 1.3 g of ethyl2-(6-aminochroman-2-yl)acetate hydrochloride (about 80% yield).

Example 16

Production of ethyl chromone-2-carboxylate

Into a solution of 12.0 g of diethyl oxalate in 180 g of toluene isadded 30 g of 2-hydroxyacetophenone, then dropwise added 65.0 g of 20%sodium ethoxide in ethanol. After the reaction is complete, 13 g of 98%sulfuric acid is added, and the mixture stirred at 60° C. for about 30min. After adding 140 g of water, the organic fraction is separated. Theorganic fraction is concentrated and 55.0 g of hexane is added.Filtering below 10° C. affords about 34.0 g of ethylchromone-2-carboxylate (about 95% yield).

Example 17

Production of ethyl 6-nitrochromone-2-carboxylate

To a solution of ethyl chromone-2-carboxylate (Example 16) in about 3 mLof sulfuric acid cooled to −10° C. is added about 1 mL potassium nitratein sulfuric acid. The molar ratio of potassium nitrate to the benzopyranis slightly greater than 1:1. The reaction mixture is stirred at 0° C.for 1 h, the ice bath removed, and the reaction stirred at roomtemperature until the reaction is complete by HPLC (<3% benzopyran):about 4-6 h. The nitrated benzopyran precipitates as the reactionprogresses. The reaction mixture is poured onto ice, and the precipitateis dissolved in ethyl acetate. The ethyl acetate layer is dried,filtered, and evaporated to afford ethyl 6-nitrochromone-2-carboxylateas a light yellow solid (about 90% yield).

Example 18

Production of 6-amino-2-hydroxymethylchromane

To a stirred solution of 11.4 grams (61.7 mmol) of6-aminochroman-2-carboxylic acid in 100 mL of THF was slowly added 6.64g (122 mmol) of lithium aluminum hydride. The mixture was refluxed for30 min, then quenched with ethyl acetate and 150 mL of 1 N HCl.Sufficient 12 N HCl was added to completely dissolve all of theinorganic precipitates. The aqueous phase was extracted twice with ethylacetate, and the organic fractions combined, washed twice with brine,and concentrated in vacuo to an oil. This oil was distilled to afford9.28 g of 6-amino-2-hydroxymethylchromane as a clear oil thatcrystallizes on cooling (87.6% yield).

The procedures above may be altered to use different starting materials,such as those having different substituents at the 6-position (amino,protected amino, hydrogen, etc.) Additionally, other minor modificationsmay be done, such as to substitute the diethyl ester of malonic acid forthe oxalic acid diester in Examples 10 and 16, and/or to use anon-nitrated ring so as to produce a starting material as in Scheme IV.Chiral catalysts or other reduction/hydration methods may be utilizedwhich allow one to achieve enantiomerically enriched or substantiallyenantiomerically pure products and intermediates. Furthermore, otheralcohols may be used to make other esters, or the esters may behydrolyzed to provide the free acid.

In view of the above description it is believed that one of ordinaryskill can practice the invention. The examples given above arenon-limiting in that one of ordinary skill in view of the above willreadily envision other permutations and variations on the inventionwithout departing from the principal concepts. Such permutations andvariations are also within the scope of the present invention.

1. A process for making a compound according to the formula

wherein R is H or an alkyl group, comprising: (a) hydrogenating acompound of the formula:

 to produce a compound of the formula:

(b) reducing the carboxylic acid of compound of (a) to afford a compoundas follows:

(c) transforming the hydroxyl group of compound of (b) into a leavinggroup to afford a compound as follows:

 wherein OLG is a leaving group; (d) reacting the compound of (c) withcyanide ion to afford a compound as follows:

(e) hydrolyzing the compound of (d) to afford a compound as follows:


2. The process according to claim 1, wherein the hydrogenation of stepa) is performed with H₂/Pd/C.
 3. The process according to claim 1.wherein the reduction step b) is performed with a chemical reducingagent.
 4. The process according to claim 3, wherein the chemicalreducing agent is a reagent selected from the group consisting oflithium aluminum hydride, borane, and aluminum hydride.
 5. The processaccording to claim 1, wherein the OLG of step c) is a group selectedfrom the group consisting of tosylate, mesylate, and halogen.
 6. Theprocess according to claim 5, wherein the OLG is tosylate.
 7. Theprocess according to claim 1, wherein the hydrolysis step e) isperformed with heating the compound of step d) in aqueous mineral acid.8. The process according to claim 7, wherein the mineral acid ishydrochloric acid.
 9. The process according to claim 1, furthercomprising (f) converting the acid group to an ester group, wherein stepe) and step f) are performed in one reaction mixture containing reagentscomprising a mineral acid and an alcohol.
 10. The process according toclaim 9, wherein the mineral acid is hydrochloric acid and the alcoholis ethanol.
 11. A process for making a compound according to the formula

wherein R is H or an alkyl group, comprising: (a) halogenating acompound of the formula:

 to produce a 2-hydroxy chromane compound of the formula:

 wherein X is a halogen; (b) reacting the compound of (a) with cyanideion to afford a compound as follows:

(c) hydrolyzing the compound of (b) to afford a compound as follows:

(d) reducing the keto group and nitro groups of compound of (c) byhydrogenation to afford a compound as follows:


12. The process according to claim 11, wherein the halogenation step (a)is performed with thionyl chloride, thereby producing a compound of theformula:


13. The process according to claim 11, wherein the hydrolysis step (c)is performed with heating the compound of step h) in aqueous mineralacid.
 14. The process according to claim 13, wherein the mineral acid ishydrochloric acid.
 15. The process according to claim 11, wherein thehydrogenation of step (d) is performed with H₂/Pd/C.
 16. The processaccording to claim 11, further comprising (e) adding an alkyl group toform an ester, wherein (e) is performed with a mineral acid and analcohol.
 17. The process according to claim 16, wherein the mineral acidis hydrochloric acid and the alcohol is ethanol.
 18. A process formaking a compound according to the formula

wherein R is H or an alkyl group, comprising: (a) hydrogenating acompound of the formula and adding a protecting group to a subsequentlyformed amine:

 to produce a compound of the formula:

 wherein PG is the protecting group; (b) reducing the ketone of thelactone of compound of (a) to afford a compound as follows:

(c) transforming the hydroxyl group of compound of (b) into a carbonchain with a carbon nucleophile to afford a compound as follows:

 wherein R is an alkyl group; (d) hydrolyzing the compound of (c) toremove the alkyl group from the ester to afford a compound as follows:

(e) removing the protecting group from the amine, thereby obtaining thecompound of the formula:


19. The process according to claim 18, wherein the hydrogenation step a)is performed with H₂/Pd/C.
 20. The process according to claim 18,wherein the reduction step b) is performed with a chemical reducingagent.
 21. The process according to claim 20, wherein the chemicalreducing agent is DIBAL-H.
 22. The process according to claim 18,wherein the carbon nucleophile of step c) is a phosphorus ylide.
 23. Theprocess according to claim 22, wherein the phosphorus ylide is(carbethoxymethylene)triphenylphosphine.
 24. The process according toclaim 18, wherein PG is a group selected from the group consisting oft-BOC and acetyl.
 25. The process according to claim 1, for making acompound according to the formula:

in greater than 95% enantiomeric purity with respect to thecorresponding (2R) enantiomer, further comprising: (i) resolving theracemate; and (ii) forming the hydrochloride salt of the amine of theresolved compound.
 26. The process according to claim 25, wherein theracemate comprises a nitro compound or an amine compound.
 27. Theprocess according to claim 25, comprising resolution occurring with anenzyme by an enzymatic cleavage of one enantiomer over the otherenantiomer.
 28. The process according to claim 25, comprising resolutionoccurring by hydrolyzing the ester to a carboxylic acid, reacting thecarboxylic acid with a chiral reagent to form a salt; and precipitatingthe salt of one enantiomer, thereby separating one enantiomer over theother enantiomer.
 29. A process for making a compound according to theformula

wherein R is an alkyl group and Z is a counterion to the amine salt,further comprising: (a) hydrogenating the compound of the formula:

 wherein Y is a nitro, amino or protected amino group, with a chiralcatalyst to afford a compound as follows:

(b) reducing the nitro group of compound of (a) by hydrogenation toafford a compound as follows or removing the amino protecting group toproduce a compound of the formula:

(c) forming the amine salt by reaction of compound of (b) with a mineralacid.
 30. The process according to claim 29 wherein the chiral catalystcomprises ruthenium, rhodium, palladium or platinum.
 31. The processaccording to claim 29 wherein the chiral catalyst comprises BINAP. 32.The process according to claim 29 wherein the chiral catalyst is areagent selected from the group consisting of


33. The process according to claim 29 wherein the hydrogenation step g)is performed with H₂/Pd/C.
 34. The process according to claim 29 whereinthe mineral acid of step h) is hydrochloric acid.
 35. The processaccording to claim 1, further comprising (f) converting the acid groupto an ester group.
 36. The process according to claim 11, furthercomprising (e) adding an alkyl group to form an ester.
 37. The processaccording to claim 18, further comprising (f) adding an alkyl group toform an ester.
 38. The process according to claim 11, for making acompound according to the formula:

in greater than 95% enantiomeric purity with respect to thecorresponding (2R) enantiomer, further comprising: (i) resolving theracemate; and (ii) forming the hydrochloride salt of the amine of theresolved compound.
 39. The process according to claim 38, wherein theracemate comprises a nitro compound or an amine compound.
 40. Theprocess according to claim 38, comprising resolution occurring with anenzyme by an enzymatic cleavage of one enantiomer over the otherenantiomer.
 41. The process according to claim 38, comprising resolutionoccurring by hydrolyzing the ester to a carboxylic acid, reacting thecarboxylic acid with a chiral reagent to form a salt; and precipitatingthe salt of one enantiomer; thereby separating one enantiomer over theother enantiomer.
 42. The process according to claim 18, for making acompound according to the formula:

in greater than 95% enantiomeric purity with respect to thecorresponding (2R) enantiomer, further comprising: (i) resolving theracemate; and (ii) forming the hydrochloride salt of the amine of theresolved compound.
 43. The process according to claim 42, wherein theracemate comprises a nitro compound or an amine compound.
 44. Theprocess according to claim 42, comprising resolution occurring with anenzyme by an enzymatic cleavage of one enantiomer over the otherenantiomer.
 45. The process according to claim 42, comprising resolutionoccurring by hydrolyzing the ester to a carboxylic acid, reacting thecarboxylic acid with a chiral reagent to form a salt; and precipitatingthe salt of one enantiomer; thereby separating one enantiomer over theother enantiomer.